Drug-Induced Thrombocytopenia

Richard H. Aster

James N. George

BACKGROUND

Drugs induce thrombocytopenia through various mechanisms. The inhibition of platelet production is an expected result of the dose-dependent toxicity of chemotherapeutic agents. Rarely, pancytopenia (aplastic anemia) results from idiosyncratic drug hypersensitivity. A few drugs suppress platelet production selectively. A much larger number cause thrombocytopenia by promoting platelet destruction that can be acute and severe and is usually caused by drug-dependent antibodies. Mechanisms by which drugs are known to cause thrombocytopenia are summarized in Table 62.1.

In this chapter, we consider drug-induced thrombocytopenia according to pathogenesis, clinical presentation, diagnosis, and treatment. The drug implicated most often as a cause of thrombocytopenia is heparin. Heparin-induced thrombocytopenia (HIT) has a unique pathogenesis, and thrombosis, rather than thrombocytopenia, is the major concern in patients with this condition. HIT is discussed in Chapter 108 and is mentioned here only briefly.

INCIDENCE

The annual incidence of drug-induced thrombocytopenia has been estimated in four studies to be approximately 1 case per 100,000 annually¹^,²^,³^,⁴ (Table 62.2). However, these data are the result of reporting to national surveillance groups or reviewing hospital records. It can be reasonably assumed that many patients suspected of having drug-induced thrombocytopenia are not reported and that affected patients often do not require hospitalization. It is likely therefore that published estimates greatly underestimate the frequency of this condition. Another cause of underestimation may be the tendency to misdiagnose drug-induced thrombocytopenia as acute autoimmune thrombocytopenic purpura (AITP).⁵

SUPPRESSION OF PLATELET PRODUCTION BY DRUGS

Chemotherapeutic Agents

Thrombocytopenia is a common, dose-dependent side effect of chemotherapy used for treatment of cancer and for immunosuppression. All myeloid elements are likely to be affected, but thrombocytopenia is often dose limiting. Various cytokines and leukokines, including IL-6 and IL-11, have been used to reduce the severity of thrombocytopenia in patients receiving chemotherapy,⁶ but only IL-6 has been approved for this purpose. Thrombopoietin receptor agonists are not yet approved but show promise and are in various stages of evaluation.⁷ Profound thrombocytopenia sometimes occurs in patients treated with antiviral agents such as azidothymidine used to treat human immunodeficiency virus infection.

It should not be assumed a priori that thrombocytopenia associated with chemotherapy is caused by inhibition of megakaryocytopoiesis. Patients have been described who experienced an acute and very severe drop in platelet levels when treated with agents such as oxaliplatin, cyclosporine A, irinotecan, and suramin despite the demonstration of adequate numbers of megakaryocytes in aspirated bone marrow.⁸ In such instances, appropriate serologic testing may demonstrate the presence of drug-dependent, platelet-reactive antibodies capable of causing platelet destruction when drug is administered. Systemic reactions such as chills, fever, and hypotension occurring at the time of drug administration can provide a clue to the presence of such an antibody.

Drug-Induced Aplastic Anemia

Numerous medications are thought to be capable of causing aplastic anemia on an idiosyncratic basis. Implicated drugs include anticonvulsants, nonsteroidal anti-inflammatory drugs, and sulfonamides. The pathogenesis of this complication is poorly understood,⁹^,¹⁰ and there is at present no means of identifying patients at risk to develop this complication.

Drugs that Selectively Inhibit Megakaryocytopoiesis

Alcohol

Thrombocytopenia, sometimes severe, is common in persons who ingest large quantities of alcohol for long periods of time.¹¹ Although vitamin deficiency and/or splenomegaly and cirrhosis contribute to the lowering of platelet levels in some cases, there is evidence that ethanol can directly affect megakaryocytopoiesis. In general, thrombocytopenia is mild in patients with chronic alcoholism, but very low platelet counts and bleeding have been described. After abstinence for a few weeks, platelet levels usually return to the normal range, but moderate thrombocytopenia persists for longer periods in some patients.

Estrogens

Large doses of estrogens adversely affect megakaryocytopoiesis, leading to profound thrombocytopenia in some species of animals, especially dogs.¹² Rare cases of thrombocytopenia associated with megakaryocyte dysplasia in humans treated
with estrogens have been described. It has been suggested that estrogens can exacerbate thrombocytopenia in women with autoimmune thrombocytopenia.

Table 62.1 Classification of drug-induced thrombocytopenia

Decreased Platelet Production

Generalized suppression of hematopoiesis (dose-dependent toxicity; e.g., chemotherapeutic agents)

Idiosyncratic aplastic anemia (e.g., anticonvulsants, sulfonamides, nonsteroidal anti-inflammatory drugs)

Selective suppression of platelet production (e.g., anagrelide, valproic acid)

Platelet destruction through nonimmune mechanisms (e.g., desmopressin, protamine sulfate)

Platelet Destruction Through Immune Mechanisms

Hapten-dependent antibodies (penicillin?)

“Quinine-type” immune thrombocytopenia (e.g., quinine, sulfamethoxazole, vancomycin, piperacillin

Drug-induced, platelet-specific autoantibodies (e.g., gold salts, procaine amide)

Thrombocytopenia in patients treated with ligand-mimetic platelet inhibitors (e.g., tirofiban, eptifibatide)

Abciximab-induced thrombocytopenia

Drug-induced immune complexes (heparin)

Histone Deacetylase Inhibitors

Histone deacetylase inhibitors (HDACi), a new class of chemotherapeutic drugs, regularly produce a degree of thrombocytopenia in treated patients, an effect that limits their use in some individuals.¹³ Animal studies suggest that HDACi act directly on megakaryocytes to inhibit maturation and proplatelet formation¹³ through a mechanism not fully understood. Preclinical studies provide evidence that HDACi-induced thrombocytopenia can be ameliorated by treatment with a thrombopoietin receptor agonist. Valproic acid, although mainly used as an anticonvulsant, is an HDACi and causes mild thrombocytopenia in up to one-third of treated individuals.¹⁴ Rarely, thrombocytopenia is acute and severe.

Linezolid

Linezolid is an oxazolidinone antibiotic used for treatment of drug-resistant bacterial infections. Low-grade thrombocytopenia occurs in 30% to 40% of individuals treated with this drug for more than 10 days.¹⁵ Patients with renal dysfunction and those given the drug intravenously¹⁵ are more likely to experience a reduction in platelet levels. There is evidence that linezolid acts to suppress megakaryocytopoiesis through a dose-dependent mechanism.

Table 62.2 Incidence of drug-induced thrombocytopenia

Country	Years	Method	Annual Incidence
Sweden^a	1966-1970	Reports to Swedish Adverse Reaction Committee	1/100,000
Denmark^b	1968-1991	Reports to Danish Committee on adverse drug reactions	1/100,000
USA^c	1972-1981	Hospital records, Puget Sound Group Health Cooperative	0.6/100,000
USA^d	1983-1991	Hospital records, case control study	1.8/100,000
^aBottiger LE, Bottiger B. Incidence and cause of aplastic anemia, hemolytic anemia, agranulocytosis and thrombocytopenia. Acta Med Scand 1981;210:475-479. ^bPedersen-Bjergaard U, Andersen M, Hansen PB. Drug-specific characteristics of thrombocytopenia caused by noncytotoxic drugs. Eur J Clin Pharmacol 1998;54:701-706. ^cDanielson DA, Douglas SW III, Herzog P, et al. Drug-induced blood disorders. JAMA 1984;252:3257-3260. ^dKaufman DW, Kelly JP, Johannes CB, et al. Acute thrombocytopenic purpura in relation to the use of drugs. Blood 1993;82:2714-2718.

Imatinib Mesylate

Thrombocytopenia, often accompanied by neutropenia, occurs in up to 70% of patients treated with imatinib mesylate for chronic myelogenous leukemia.¹⁶ The mechanism of this effect is poorly understood. Responses to granulocyte colony stimulating factor and IL-11 have been described.

Anagrelide

The quinazoline compound anagrelide causes isolated thrombocytopenia with little effect on other aspects of hematopoiesis.¹⁷ Animal studies suggest that anagrelide interferes with megakaryocyte maturation, possibly through the action of a metabolite, an effect that makes it useful for treating thrombocythemia in patients with myeloproliferative conditions. In rare cases, profound thrombocytopenia has occurred in patients given anagrelide for this purpose.

Interferons

Low-grade thrombocytopenia is a common side effect of interferon therapy. Profound thrombocytopenia and bleeding have been described in patients with chronic hepatitis C given interferon α and pegylated interferon-2b.¹⁸ Interferons α and γ inhibit megakaryocyte proliferation in cell culture models and stem cell differentiation in animals, but whether this is relevant to thrombocytopenia developing in patients treated with interferons is uncertain.

DRUG-INDUCED PLATELET DESTRUCTION THROUGH NONIMMUNE MECHANISMS

Leukokines and Hematopoietic Growth Factors

An acute drop in platelet levels has been described in patients treated with granulocyte-macrophage colony-stimulating factor. Activation of macrophages and monocytes in the liver and spleen has been implicated as a possible cause. Macrophage colony-stimulating factor may exert a similar effect in rare individuals.

Tumor Necrosis Factor α and Interferon γ

Acute, severe thrombocytopenia has been described in a small number of patients following treatment of Ewing sarcoma with tumor necrosis factor α combined with interferon γ. A direct effect of the cytokines on endothelium, leading to increased platelet clearance has been postulated as a possible mechanism.

Porcine Factor VIII

Patients given porcine factor VIII for treatment of hemophilia often experience mild thrombocytopenia. Occasionally, a profound drop in platelet levels occurs. Hypersensitivity symptoms such as chills, fever, and urticaria sometimes accompany these reactions. Bovine von Willebrand factor (vWF) contaminating the Factor VIII preparations has been implicated. Whether xenoantibodies specific for porcine factor VIII contribute to this effect has not been established.

Desmopressin

Desmopressin (DDAVP) is used for treatment of some patients with von Willebrand disease (vWD) because of its ability to induce vWF release from endothelial cells.¹⁹ Patients with type 2B vWD, who possess a vWF mutant that binds to the platelet vWF receptor with high affinity, sometimes experience severe thrombocytopenia after treatment with DDAVP. Patients with “platelettype” vWD, who have a mutant vWF platelet receptor, can also develop thrombocytopenia following DDAVP administration.

Protamine Sulfate

Protamine sulfate is widely used to neutralize circulating heparin following open-heart surgery. Mild thrombocytopenia often develops after protamine administration, but it can be difficult to ascertain whether this is a consequence of protamine infusion or is representative of low-grade thrombocytopenia routinely seen after this procedure. However, sequestration of indium 111-labeled platelets in the liver was demonstrated in a cohort of patients given protamine. Protamine is known to bind to chondroitin sulfate normally found on the platelet surface²⁰ but whether this interaction is related to transient platelet sequestration following protamine infusion is uncertain.

Amrinone

The pyridine phosphodiesterase-3 inhibitor amrinone is widely used for treatment of heart failure. Up to one-third of individuals given amrinone experience low-grade thrombocytopenia soon after starting the drug. The mechanism of this effect is uncertain, but the N-acetyl metabolite of the drug was implicated in one study.

DRUG-INDUCED PLATELET DESTRUCTION THROUGH IMMUNE MECHANISMS

Pathogenesis

As summarized in Table 62.3, drug-dependent, antibody-mediated immune thrombocytopenia is caused by several distinctly different mechanisms.

Hapten-Dependent Antibodies

It is generally thought that low molecular weight compounds like drugs induce antibodies only when they are covalently linked to a larger carrier molecule, usually a protein. Accordingly, it was assumed for many years that immune thrombocytopenia in patients sensitive to drugs is caused by antibodies raised against drug covalently linked to a platelet membrane glycoprotein. However, antibodies identified in such patients did not exhibit the behavior expected of a hapten-dependent immunoglobulin since they could not be inhibited by excess concentrations of drug and they failed to react with platelets pretreated with drug and then washed. It is now thought that classical “hapten-dependent antibodies” rarely, if ever, cause immune thrombocytopenia. However, penicillin and penicillin derivatives, which spontaneously form covalent linkages with cell membrane proteins, do on occasion induce true hapten-dependent antibodies capable of causing immune hemolytic anemia.¹⁰ By analogy, it is possible that thrombocytopenia occurring rarely in patients treated with penicillin and structurally similar drugs is caused by this mechanism. However, this has not been confirmed experimentally.

“Quinine-Type” Immune Thrombocytopenia

Sudden and sometimes life-threatening thrombocytopenia following treatment with medication was described as a clinical entity more than 120 years ago. The responsible antibodies are unusual in that they are completely harmless in the absence of drug, but in its presence, bind tightly to specific platelet membrane glycoproteins and cause platelet destruction.⁸^,²¹ Several hundred different drugs have been implicated, but quinine, quinidine, various antibiotics, nonsteroidal anti-inflammatory drugs, and the chemotherapeutic drug oxaliplatin are among those that trigger this condition most often.⁸^,²¹^,²² Since quinine is the prototypic drug associated with this condition, we will refer to it as “quinine-type” thrombocytopenia. Antibodies found in patients with “quinine-type” thrombocytopenia are unique among pathogenic immunoglobulins in several respects: (a) They bind tightly to epitopes on platelet membrane glycoproteins at the highest
achievable drug concentration, rather than being inhibited as might be expected of a “hapten-dependent” antibody. (b) They fail to recognize platelets pretreated with the sensitizing drug. (c) They recognize only glycoproteins found on human or primate platelets. (d) They dissociate from the target glycoprotein upon being suspended in buffer in the absence of drug.⁸^,²³

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